Effects of [gamma]-secretase cleavage-region mutations on APP processing and A[beta] formation: interpretation with sequential cleavage and [alpha]-helical model

• Published in: Journal of neurochemistry 2008-11, Vol.107 (3), p.722
• Main Authors: Tan, Jianxin, Mao, Guozhang, Cui, Mei-Zhen, Kang, Shin-Chung, Lamb, Bruce, Wong, Boon-Seng, Sy, Man-Sun, Xu, Xuemin
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Biochemistry; Mutation; Neurology; Peptides
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05643.x

Overwhelming evidence supports the amyloid hypothesis of Alzheimer's disease that stipulates that the relative level of the 42 amino acid [beta]-amyloid peptide (A[beta]42) in relationship to A[beta]40 is critical to the pathogenesis of the disease. While it is clear that the multi-subunit gamma secretase is responsible for cleavage of the amyloid precursor protein (APP) into A[beta]42 and A[beta]40, the exact molecular mechanisms regulating the production of the various A[beta] species remain elusive. To elucidate the underlying mechanisms, we replaced individual amino acid residues from positions 43 to 52 of A[beta] with phenylalanine to examine the effects on the production of A[beta]40 and A[beta]42. All mutants, except for V50F, resulted in a decrease in total A[beta] with a more prominent reduction in A[beta] for residues 45, 48, and 51, following an every three residue repetition pattern. In addition, the mutations with the strongest reductions in total A[beta] had the largest increases in the ratio of A[beta]42/A[beta]40. Curiously, the T43F, V44F, and T48F mutations caused a striking decrease in the accumulation of membrane bound A[beta]46, albeit by a different mechanism. Our data suggest that initial cleavage of APP at the [epsilon] site is crucial in the generation of A[beta]. The implicated sequential cleavage and an [alpha]-helical model may lead to a better understanding of the [gamma]-secretase-mediated APP processing and may also provide useful information for therapy and drug design aimed at altering A[beta] production. [PUBLICAITON ABSTRACT]